Metastases in the Breast from Nonmammary Malignant Neoplasms

Metastases in the Breast from Nonmammary Malignant Neoplasms

Syed A. Hoda

The preoperative clinical workup of an apparently healthy patient with a breast mass can be cursory and is unlikely to exclude a metastasis from a clinically inapparent (that is, “occult”) nonmammary malignant neoplasm (NMMN). Even if a history of a previously treated NMMN is known to the clinician when a needle core biopsy (NCB) is obtained, this information may not be conveyed to the pathologist. Thus, when faced with a mammary neoplasm that has unusual clinical, radiologic, or histologic features, it is important to consider metastasis in the differential diagnosis.


Metastases from NMMN are rare and account for less than 1% of all mammary malignant neoplasms in clinical series, and up to 5% of autopsies of patients who die as a result of NMMN (1). Such tumors are relatively more common in females. The interval between initial diagnosis of a NMMN and mammary metastases is usually about 2 years—but it can vary from a few weeks to several years. In approximately one-third of the cases, the metastasis in the breast is the first presentation of the NMMN. Usually, there have already been metastases at other sites, or the tumors are detected at various sites synchronously (2,3).

Metastatic foci in breast often present initially as solitary masses (2). Upon disease progression, such tumors can become multiple and bilateral (3). Metastases have been described in the ipsilateral axillary lymph nodes in a substantial proportion of patients with metastases in the breast (2).

Hematopoietic and lymphoid neoplasms involving the breast are sometimes listed under the rubric of breast “metastases,” but they are best regarded as either primary breast neoplasms or as a manifestation of a systemic condition, depending upon the extent of organ involvement. If hematopoietic and lymphoid neoplasms are excluded, the most common NMMNs that secondarily involve the breast include carcinomas of the lung, ovary, stomach, kidney, and cutaneous melanoma. Metastasis from the contralateral breast is a diagnostic consideration when there is bilateral involvement (or history thereof), the histologic appearances of the tumors in the breasts are similar, and there is no evidence of in situ carcinoma in the contralateral breast. In the pediatric population, lymphoma and rhabdomyosarcoma are the most common sources of NMMN in the breast.


On mammography, metastatic tumors tend to present as discrete, solitary, or multiple round masses without spiculation (3). As a result, metastatic tumors cannot be distinguished radiologically from circumscribed primary breast carcinomas, particularly those of the papillary, medullary, or mucinous types. Calcific deposits are uncommon in metastases from NMMN but may occur in metastatic mullerian (tubal, ovarian, or peritoneal) carcinomas (4,5). Ultrasonography typically shows the lesions to be hypoechoic without spiculations (6). Radiologic techniques such as MRI (magnetic resonance imaging) and FDG-PET/CT (fluorodeoxyglucose-positron emission tomography-computed tomography) have also detected metastases in the breast from carcinoma of the thyroid (7), ovary (8), and soft tissue liposarcoma (9). In the latter two instances, the diagnosis of a metastatic NMMN was confirmed by a NCB.


The histopathologic appearance of NMMN in the breast is seldom specifically indicative of the site of origin. A notable exception is pigmented metastatic melanoma, although pigmented melanocytic differentiation can occur in metaplastic mammary carcinoma (10). Melanoma arising in the breast is usually a form of metaplastic carcinoma, and it may therefore express cytokeratin. Noncytokeratin expressing primary melanoma of the breast is neurogenic in origin and cytokeratin-negative. Nonetheless, primary melanocytic lesions of the breast are exceedingly less common than metastatic melanocytic neoplasms.

Among the metastatic carcinomas in the breast that are most likely to be mistaken for a breast primary are those arising in the lung, ovary, mullerian system, and bowel. Included in this group are mucinous, signet ring cell, clear cell, and poorly differentiated non-small cell carcinomas of various organs, as well as malignant melanoma (11). Some types of breast tumors such as small cell, adenoid cystic, and mucoepidermoid carcinomas can occur in other organs, and appropriate clinical workup is prudent in these cases. Metastatic neuroendocrine carcinomas of various organs generally share histologic features with primary mammary carcinoma (12).

Histopathologic evaluation of the limited material obtained in NCB samples is unlikely to provide all of the information that would help to distinguish between a primary and a metastatic tumor. The presence of in situ carcinoma that is histologically similar to the invasive lesion rules out a metastatic NMMN. On the other hand, the absence of in situ carcinoma in association with invasive carcinoma is supportive (but not diagnostic) of metastatic rather than a primary breast carcinoma. Metastatic tumor often surrounds and displaces histologically unremarkable breast glandular parenchyma. This phenomenon is less frequent in primary mammary ductal carcinoma, but it is encountered in invasive lobular carcinoma. The latter typically shows little or no hyperplasia. A peripheral lymphocytic infiltrate and stromal reaction are not unusual at the site of metastatic tumor in the breast as well as in primary breast carcinomas. The finding of more than two grossly evident tumor nodules should lead one to consider metastatic tumor, especially if the histologic pattern is unusual. Lymphovascular tumor emboli may result from metastases in the breast as well as from primary breast carcinomas. Diffuse lymphatic spread of metastatic tumor within the breast can occur, and rarely it produces the clinical appearance of inflammatory carcinoma (13).

An unusual histologic pattern and clinical information about a prior neoplasm are the best clues for identifying a metastatic tumor in the breast. It is important to be sensitive to histopathologic patterns that are not typical for breast carcinoma.

FIGURE 22.1 Metastatic Pulmonary Adenocarcinoma. A: Adenocarcinoma in a needle core biopsy specimen of the breast. Without a clinical history of pulmonary carcinoma, this tumor might be interpreted as mammary carcinoma. B: Intracytoplasmic mucin appears magenta with the mucicarmine stain. A histologically similar adenocarcinoma of lung had been previously diagnosed and treated.


Carcinoma of the Lung and Mesothelioma

Non-small cell carcinoma of the lung is among the most common NMMN to metastasize to the breast (14,15,16,17). Pulmonary adenocarcinoma has diverse histologic appearances some of which resemble mammary carcinoma (Fig. 22.1). Knowledge of any synchronously or metachronously occurring carcinoma of the lung as well as comparative histopathologic review of the concurrent or prior lung tumor are vital aides in this circumstance (18).

About 75% of pulmonary carcinomas are positive for thyroid transcription factor (TTF1). Although TTF1 immunoreactivity has been reported in mammary carcinomas, the main factor influencing the purported prevalence of TTF1 expression in tumors other than those of pulmonary and thyroid origin is the type of clone used. It has been reported that clone SPT24 (Leica/Novocastra) is more sensitive but less specific than clone 8G7G3/1 (Dakocytomation) (19). Napsin A can be confirmatory of lung primary (20).

Small cell carcinoma can be primary or metastatic in the breast. The diagnosis of primary small cell carcinoma of the breast is supported by the concurrent presence of a conventional ductal type of invasive and/or in situ carcinoma. The diagnosis of metastatic small cell carcinoma in the breast from another organ including lung can be rendered by the exclusion of a mammary primary and comparative histopathologic review of the nonmammary primary tumor. Immunohistochemical stains are unhelpful in this regard since most nonpulmonary (including mammary) small cell carcinomas are ER (-), PR (-), and TTF1 (+). Metastatic small carcinoma is more often multifocal and multicentric.

An exceedingly rare source of metastatic tumor in the breast is mesothelioma, especially the epithelioid variant that may mimic a mammary primary. Immunoreactivity for D2-40 (podoplanin) and calretinin strongly favors mesothelioma
over carcinoma (21). Other stains that are helpful to confirm the diagnosis of mesothelioma include claudin-4, CD15, and MOC-31 (21,22,23,24).

Malignant Melanoma

Metastatic malignant melanoma presenting clinically as a breast tumor may be difficult to recognize if the primary (cutaneous or ocular) lesion is occult or if the pathologist is uninformed of the clinical history (Fig. 22.2) (25). Metastatic melanoma has been reported in the male breast, and it may also involve axillary lymph nodes (2). As stated earlier, exceedingly rare examples of metaplastic mammary carcinoma display melanocytic differentiation (10).

Gastrointestinal Neoplasms

Adenocarcinomas originating in the gastrointestinal tract, especially in the colon and rectum, are rarely the source of metastatic carcinoma in the breast, despite their relatively higher prevalence (26,27,28). In this setting, nuclear immunoreactivity for CDX2 is supportive of the diagnosis of metastatic colorectal adenocarcinoma (Fig. 22.3) (29).

FIGURE 22.2 Metastatic Malignant Melanoma. A, B: Diffusely infiltrating malignant cytokeratin-negative (not shown) cells with an epithelioid appearance. C: The tumor cells are immunoreactive for HMB-45. D-E: Metastatic spindle and epithelioid melanoma in another needle core breast biopsy sample. The spindle cell component is reactive for S-100 protein (F). There was no reactivity for HMB-45 or Melan-A (not shown). G-H: Histopathologic diversity of metastatic melanoma is evident in two additional needle core biopsy specimens of the breast. The melanoma cells appear epithelioid and relatively cohesive in (G), and are discohesive and pigmented in (H).

Neuroendocrine (“carcinoid”) tumors of the gastrointestinal tract are a surprisingly frequent source of metastases in one or both breasts (12,30,31). Without knowledge of an extramammary primary, a metastatic neuroendocrine tumor in the breast can be mistaken for a mammary carcinoma with neuroendocrine differentiation (32), or for invasive lobular carcinoma.

Neoplasms of Gynecological Organs

Serous carcinomas of mullerian (that is, tubo-ovarian or peritoneal) origin usually display a papillary appearance with abundant psammoma bodies (Fig. 22.4). The typical immunoprofile of these neoplasms is CK7 (+), CK20 (-), CA125 (+), WT1 (+), and PAX8 (+). The final diagnosis depends on clinical and radiologic correlation (4,33,34,35). Clinically, occult serous carcinomas of tubal origin can present with axillary lymph nodal involvement (36). Mullerian carcinomas in the breast have generally been serous rather than mucinous. Metastatic endometrial carcinoma with a solid growth pattern
may mimic poorly differentiated or solid papillary mammary carcinoma (Fig. 22.5) (37).

FIGURE 22.2 (continued)

FIGURE 22.3 Metastatic Adenocarcinoma in a Patient with a Known Primary Tumor of Sigmoid Colon. A, B: This needle core biopsy of the breast shows adenocarcinoma. A cluster of native benign inactive breast glands is evident (top center). The tumor cells are immunoreactive with CDX2 (inset in B)—a result that is supportive of the diagnosis of metastatic colonic carcinoma. (Courtesy of Drs. S. Titi and A. Ahmad.)

The immunostain for WT1 (Wilms tumor suppressor gene 1), a nuclear marker associated with mullerian (that is, tubo-ovarian and peritoneal) serous papillary carcinomas, has not been reported to be reactive in mammary carcinomas (35,38,39), with the exception of rare cases of invasive micropapillary carcinoma (40,41). This is of interest because of the reported upregulation of the WT1 gene in breast carcinomas (42,43), and the observation that higher WT1 messenger ribonucleic acid (mRNA) levels were associated with a relatively poor prognosis in a series of 99 breast carcinoma patients with

a median follow-up of 48 months (44). Focal cytoplasmic reactivity for WT1 in breast carcinomas noted in one report (42) is not considered to be a positive result. Because the majority of mullerian carcinomas are CA125-positive and WT1 is negative in most mammary carcinomas, nuclear reactivity for WT1 and cytoplasmic reactivity for CA125 strongly favors metastatic mullerian carcinoma over primary mammary carcinoma (14,40).

FIGURE 22.4 Metastatic Ovarian Carcinoma. A: Part of needle core biopsy of the breast with metastatic papillary serous ovarian carcinoma. B, C: This needle core biopsy sample of the breast shows metastatic poorly differentiated ovarian carcinoma with a solid architecture that resembles mammary carcinoma. D: This biopsy of an axillary lymph node shows metastatic papillary serous carcinoma of the ovary with calcifications. PAX8 positivity is shown in inset.

FIGURE 22.5 Metastatic Endometrial Carcinoma. A, B: The solid growth pattern divided into alveolar nests in this needle core biopsy of metastatic endometrial carcinoma resembles the structure of solid papillary mammary carcinoma.

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Nov 17, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Metastases in the Breast from Nonmammary Malignant Neoplasms

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